Clinical Trials /

Irinotecan Hydrochloride, Temozolomide, and Dinutuximab With or Without Eflornithine in Treating Patients With Relapsed or Refractory Neuroblastoma

NCT03794349

Description:

This phase II trial studies how well irinotecan hydrochloride, temozolomide, and dinutuximab work with or without eflornithine in treating patients with neuroblastoma that has come back or that isn't responding to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as dinutuximab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Eflornithine blocks the production of chemicals called polyamines that are important in the growth of cancer cells. Giving eflornithine with irinotecan hydrochloride, temozolomide, and dinutuximab, may work better in treating patients with relapsed or refractory neuroblastoma.

Related Conditions:
  • Ganglioneuroblastoma
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Irinotecan Hydrochloride, Temozolomide, and Dinutuximab With or Without Eflornithine in Treating Patients With Relapsed or Refractory Neuroblastoma
  • Official Title: A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab With or Without Eflornithine (DFMO) in Children With Relapsed, Refractory or Progressive Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: ANBL1821
  • SECONDARY ID: NCI-2018-03377
  • SECONDARY ID: ANBL1821
  • SECONDARY ID: ANBL1821
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03794349

Conditions

  • Ganglioneuroblastoma
  • Recurrent Neuroblastoma
  • Refractory Neuroblastoma

Interventions

DrugSynonymsArms
DinutuximabCh 14.18UTC, Ch14.18, MOAB Ch14.18, monoclonal antibody Ch14.18, UnituxinRegimen A (chemotherapy, dinutuximab, sargramostim)
EflornithineAlpha-Difluoromethylornithine, DFMO, difluoromethylornithine, DifluromethylornithineRegimen B (eflornithine, chemotherapy, dinutuximab)
IrinotecanRegimen A (chemotherapy, dinutuximab, sargramostim)
Sargramostim23-L-Leucinecolony-Stimulating Factor 2, DRG-0012, Leukine, Prokine, rhu GM-CFS, Sagramostim, SargramostatinRegimen A (chemotherapy, dinutuximab, sargramostim)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, TemomedacRegimen A (chemotherapy, dinutuximab, sargramostim)

Purpose

This phase II trial studies how well irinotecan hydrochloride, temozolomide, and dinutuximab work with or without eflornithine in treating patients with neuroblastoma that has come back or that isn't responding to treatment. Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as dinutuximab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Eflornithine blocks the production of chemicals called polyamines that are important in the growth of cancer cells. Giving eflornithine with irinotecan hydrochloride, temozolomide, and dinutuximab, may work better in treating patients with relapsed or refractory neuroblastoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether administration of eflornithine (DFMO) in combination with
      dinutuximab, irinotecan hydrochloride (irinotecan) and temozolomide results in an improved
      response rate compared to dinutuximab, irinotecan and temozolomide in patients with relapsed
      or refractory neuroblastoma and therefore is a therapeutic regimen worthy of further testing
      in patients with newly-diagnosed high-risk neuroblastoma.

      SECONDARY OBJECTIVES:

      I. To compare progression-free survival and overall survival between patients receiving
      dinutuximab, irinotecan and temozolomide with and without the addition of DFMO.

      II. To define the toxicity profile of DFMO administered with dinutuximab, irinotecan and
      temozolomide.

      EXPLORATORY OBJECTIVES:

      I. To characterize the immune and cytokine profiles of patients treated with
      DFMO/chemotherapy/dinutuximab combination and correlate with response to therapy.

      II. To evaluate GD2 levels in tumor cells from patient bone marrow samples and correlate with
      response to therapy.

      III. To explore whether the addition of DFMO to the dinutuximab and chemotherapy backbone
      affects pain as determined by patient report and opiate usage.

      OUTLINE: Patients are randomized to 1 of 2 regimens.

      REGIMEN A: Patients receive temozolomide orally (PO), via nasogastric (NG), or gastric (G)
      tube on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5,
      dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over
      2 hours on days 6-12 of a 28-day cycle. Treatment repeats every 21 days for up to 17 cycles
      in the absence of disease progression or unacceptable toxicity.

      REGIMEN B: Patients receive eflornithine PO, via NG, or G tube on days -6 to 21 of cycle 1
      and days 1-21 of subsequent cycles, temozolomide PO, via NG, or G tube on days 1-5,
      irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, dinutuximab IV over
      10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Treatment
      repeats 28 for cycle 1 and then every 21 days for up to 17 cycles in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and periodically for
      5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Regimen A (chemotherapy, dinutuximab, sargramostim)Active ComparatorPatients receive temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12 of a 28-day cycle. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
  • Dinutuximab
  • Irinotecan
  • Sargramostim
  • Temozolomide
Regimen B (eflornithine, chemotherapy, dinutuximab)ExperimentalPatients receive eflornithine PO, via NG, or G tube on days -6 to 21 of cycle 1 and days 1-21 of subsequent cycles, temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Treatment repeats 28 for cycle 1 and then every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
  • Dinutuximab
  • Eflornithine
  • Irinotecan
  • Sargramostim
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have had histologic verification of neuroblastoma or
             ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
             elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the time
             of initial diagnosis.

          -  For the purposes of this study, aggressive multidrug chemotherapy is defined as
             chemotherapy including 2 or more agents that must include an alkylating agent and a
             platinum-containing compound. Patients must have ONE of the following:

               -  First episode of recurrent disease following completion of aggressive multi-drug
                  frontline therapy.

               -  First episode of progressive disease during aggressive multi-drug frontline
                  therapy.

               -  Primary resistant/refractory disease (less than partial response by International
                  Neuroblastoma Response Criteria [INRC]) detected at the conclusion of at least 4
                  cycles of aggressive multidrug induction chemotherapy on or according to a
                  high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1,
                  ANBL12P1, ANBL1531, etc.).

          -  Patients must have at least ONE of the following:

               -  Measurable tumor on magnetic resonance imaging (MRI) or computed tomography (CT)
                  scan obtained within 3 weeks prior to study entry. Measurable is defined as >= 10
                  mm in at least one dimension on spiral/helical CT that is metaiodobenzylguanidine
                  (MIBG) avid or demonstrates increased fludeoxyglucose F-18 (FDG) uptake on
                  positron emission tomography (PET) scan.

               -  MIBG-avid lesion detected on MIBG scan obtained within 3 weeks prior to study
                  entry with positive uptake at a minimum of one site. This site must represent
                  disease recurrence after completion of therapy, progressive disease on therapy,
                  or refractory disease during induction.

               -  Patients with resistant/refractory soft tissue disease that is not MIBG avid or
                  does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
                  document the presence of viable neuroblastoma. Biopsy is not required for
                  patients who have a new site of soft tissue disease (radiographic evidence of
                  disease progression) regardless of whether progression occurs while receiving
                  therapy or after completion of therapy.

               -  Patients with bone marrow disease only will be eligible if they have more than 5%
                  disease involvement (documented neuroblastoma cells) in at least one sample from
                  bilateral bone marrow biopsies.

               -  Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT
                  eligible for this study.

          -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
             Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
             Lansky for patients =< 16 years of age.

          -  Primary refractory/resistant patients must have received at least 4 cycles of
             frontline chemotherapy. Frontline therapy may also have included surgery,
             chemotherapy, autologous stem cell transplantation (SCT) +/- MIBG, immunotherapy,
             radiotherapy, and retinoids but must NOT have received second line therapy for
             resistant/refractory, relapsed, or progressive disease. Patients who received
             intensified therapy for poor induction response or refractory disease (e.g. MIBG) will
             be considered to have received second line therapy and will not be eligible.

          -  At least 14 days must have elapsed since completion of myelosuppressive therapy.

          -  At least 7 days must have elapsed since the completion of therapy with a
             non-myelosuppressive biologic agent or retinoid.

          -  No interim time prior to study entry is required following prior radiation therapy
             (RT) for non-target lesions. However, patients must not have received radiation for a
             minimum of 4 weeks prior to study entry at the site of any lesion that will be
             identified as a target lesion to measure tumor response. Lesions that have been
             previously radiated cannot be used as target lesions unless there is radiographic
             evidence of progression at the site following radiation or a biopsy done following
             radiation shows viable neuroblastoma. Palliative radiation while on study is not
             permitted.

          -  Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
             infusions (including stem cell infusions given as supportive care following 131 I-MIBG
             therapy) as long as hematologic and other eligibility criteria have been met.

          -  Patients are eligible >= 6 weeks after therapeutic 131 I-MIBG provided that all other
             eligibility criteria are met.

          -  Subjects who have previously received anti-GD2 monoclonal antibodies with or without
             retinoids for biologic therapy are eligible unless they have had progressive disease
             while receiving prior anti-GD2 therapy or progressed/relapsed within 3 months of
             receiving anti-GD2 therapy. However, eligible patients may NOT have received anti-GD2
             monoclonal antibodies in combination with chemotherapy.

          -  Subjects who have received autologous marrow infusions or autologous stem cell
             infusions that were purged using monoclonal antibody linked to beads are eligible.

          -  Subjects who have previously received DFMO are eligible for this study provided they
             have not had progressive disease while receiving DFMO or progressed/relapsed within 3
             months of completing DFMO.

          -  Patients must not have received long-acting myeloid growth factors (e.g.
             pegfilgrastim) within 14 days of entry on this study. Seven days must have elapsed
             since administration of a short-acting myeloid growth factor.

          -  For patients with solid tumors (without marrow involvement) including status post SCT:
             peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to
             enrollment).

          -  For patients with solid tumors (without marrow involvement) including status post SCT:
             platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to
             enrollment).

          -  Patients known to have bone marrow involvement with neuroblastoma are eligible
             provided that minimum ANC and platelet count criteria are met. However, these patients
             are not evaluable for hematological toxicity.

          -  Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 or a serum creatinine
             based on age/gender as follows:

               -  1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)

               -  6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)

               -  1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)

               -  2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)

               -  6 to < 10 years (male 1 mg/dL, female 1 mg/dL)

               -  10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)

               -  13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)

               -  >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to
                  enrollment).

          -  Total bilirubin =< 1.5 x ULN for age (within 7 days prior to enrollment).

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
             ULN for age (=< 225 U/L). For the purpose of this study, the ULN for SGPT is 45 U/L
             (within 7 days prior to enrollment).

          -  Shortening fraction of >= 27% by echocardiography (ECHO) (within 7 days prior to
             enrollment).

          -  Ejection fraction of >= 50% by ECHO or gated radionuclide study (within 7 days prior
             to enrollment).

          -  No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
             requirement, and room air pulse oximetry > 94% if there is a clinical indication for
             pulse oximetry. Normal pulmonary function tests in patients who are capable of
             cooperating with testing (including diffusion capacity of the lung for carbon monoxide
             [DLCO)] are required if there is a clinical indication for determination. For patients
             who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT
             required.

          -  Patients with a history of central nervous system (CNS) disease must have no clinical
             or radiological evidence of active CNS disease at the time of study enrollment.

          -  Patients with seizure disorders may be enrolled if seizures are well controlled on
             anti-convulsants.

          -  CNS toxicity =< grade 2.

        Exclusion Criteria:

          -  Men and women of childbearing potential and their partners must agree to use adequate
             contraception while enrolled on this study. Based on the established teratogenic
             potential of alkylating agents, pregnant women will be excluded from this study.
             Because of potential risks to breastfed infants due to drug metabolites that could be
             excreted in breast milk, female patients who are lactating must agree to stop
             breastfeeding or will otherwise be excluded from this study. Females of childbearing
             potential must have a negative pregnancy test to be eligible for this study.

          -  Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT eligible for this
             study.

          -  Patients must have been off pharmacologic doses of systemic steroids for at least 7
             days prior to enrollment. Patients who require or are likely to require pharmacologic
             doses of systemic corticosteroids while receiving treatment on this study are
             ineligible. The only exception is for patients known to require 2 mg/kg or less of
             hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
             premedication for blood product administration in order to avoid allergic transfusion
             reactions. The use of conventional doses of inhaled steroids for the treatment of
             asthma is permitted, as is the use of physiologic doses of steroids for patients with
             known adrenal insufficiency.

        Patients on any other immunosuppressive medications (e.g. cyclosporine, tacrolimus) are not
        eligible.

          -  Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
             phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.
             Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic
             acid, or levetiracetam will be eligible.

          -  Patients who have received drugs that are strong inducers or inhibitors of CYP3A4
             within 7 days prior to study enrollment are not eligible.

          -  Patients must not have been diagnosed with myelodysplastic syndrome or with any
             malignancy other than neuroblastoma.

          -  Patients with symptoms of congestive heart failure are not eligible.

          -  Patients must not have >= grade 2 diarrhea.

          -  Patients who are unable to tolerate oral/nasogastric/gastrostomy medications will not
             be eligible for this trial. Additionally, patients with significant malabsorption will
             not be eligible for this trial.

          -  Patients must not have uncontrolled infection.

          -  Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
             reactions that required permanent discontinuation of the anti-GD2 therapy are not
             eligible.

          -  Patients with a significant intercurrent illness (any ongoing serious medical problem
             unrelated to cancer or its treatment) that is not covered by the detailed exclusion
             criteria and that is expected to interfere with the action of study agents or to
             significantly increase the severity of the toxicities experienced from study treatment
             are not eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:Up to 6 cycles (Each cycle is 21 days, with the exception of Regimen B Cycle 1 which is 28 days)
Safety Issue:
Description:Measured per revised International Neuroblastoma Response Criteria. Will be assessed by a one-sided continuity-corrected test of proportions with pooled variance to compare the response rates after 6 cycles in the two regimens, and the futility and efficacy monitoring rules. The response rate after 6 cycles will be calculated on each regimen, including placement of a 95% confidence interval. If the response rate on Regimen B is significantly better, then it will be considered a therapeutic regimen worthy of further testing in patients with newly-diagnosed high-risk neuroblastoma.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From the time of randomization to the occurrence of relapse, progressive disease, or death, assessed up to 5 years
Safety Issue:
Description:Kaplan-Meier curves of PFS will be generated by regimen and compared using log-rank tests.
Measure:Overall survival (OS)
Time Frame:From time of randomization to death, assessed up to 5 years
Safety Issue:
Description:Kaplan-Meier curves of OS will be generated by regimen and compared using log-rank tests.
Measure:Futility or efficacy (Regimen B): A one-sided O'Brien-Fleming group-sequential boundary will be used to monitor
Time Frame:Up to 5 years
Safety Issue:
Description:Futility monitoring will be performed. A one-sided O'Brien-Fleming group-sequential boundary will be used to monitor for efficacy of Regimen B if the sample size is increased to 148 eligible patients.
Measure:Incidence of adverse events >= 3 (Arm B)
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed with Common Terminology Criteria for Adverse Events version 5.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Children's Oncology Group

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